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AAIC 2022 | Blood biomarkers in Alzheimer’s disease: appropriate use recommendations
Stephen Salloway, MD, Brown University, Butler Hospital, Providence, RI, examines the advances in the clinical use of biomarkers in Alzheimer’s disease (AD) and outlines the newly published Alzheimer’s Association appropriate use recommendations for blood biomarkers in diagnosis, prognosis, and clinical trials. Blood biomarkers have shown significant promise in AD diagnosis and prognosis. For example, there is a strong correlation between plasma amyloid ratio (Abeta42/Abeta40) and the presence of amyloid in the brain, and guidelines have now been updated to reflect this. Utilizing blood-based biomarkers in pre-screening individuals for clinical trial participation is now recommended, provided AD status is confirmed through positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. Longitudinal biomarker assessment is also recommended in interventional trials. Clinically, the recommendations suggest that blood biomarkers may be used in specialized clinics as part of the diagnostic work-up, but confirmation of findings through standard clinical assessment is still necessary. More data is needed before these biomarkers can be used independently as a diagnostic tool or within primary care settings. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.
Transcript (edited for clarity)
So that’s probably the biggest news, at least that I’m aware of, from this meeting is that the advances in plasma biomarkers for Alzheimer’s is really moving forward quickly, which is really exciting. We’ve been hoping for this for many years. I think it’s going to change the way we practice. It’s going to really open the area for the modern treatment of Alzheimer’s based on a molecular diagnosis, not just a clinical diagnosis, which is going to be terrific, especially as we have new treatments available...
So that’s probably the biggest news, at least that I’m aware of, from this meeting is that the advances in plasma biomarkers for Alzheimer’s is really moving forward quickly, which is really exciting. We’ve been hoping for this for many years. I think it’s going to change the way we practice. It’s going to really open the area for the modern treatment of Alzheimer’s based on a molecular diagnosis, not just a clinical diagnosis, which is going to be terrific, especially as we have new treatments available.
So there are already two tests that are available in the clinic. They look at ratios of amyloid in the plasma of Abeta42/Abeta40, two molecular forms. And it looks like there’s a pretty good correlation between elevations in those markers and the presence of amyloid in the brain. So these tests can now be used in a variety of ways. So that’s what these new guidelines or recommendations are for how to use these at this point and what further information is needed so we can use them eventually independently.
I think right now, as we have new drugs for Alzheimer’s that lower amyloid that require … oh, that’s the other thing that’s in the new FDA prescribing information is that confirmation of elevated amyloid is required for treatment. That was not in the initial FDA guidance, but now it is. And we really appreciate them making that clear to clinicians. So, that’s another change in the standard of care is we’re going to need to confirm amyloid pathology. Currently we do that with an amyloid PET scan or with looking in spinal fluid. And both of those are highly sensitive and specific.
It turns out that blood biomarkers I think could be used and we’re recommending they be used to pre-screen. So people who are considering aducanumab, or if another drug gets approved this year. Another agent in this class can have a blood test first, see if they’re likely to be amyloid positive on a PET scan or spinal fluid. And then only those that look positive will then go on and have the PET scan or the spinal tap. That’s going to save a lot of money. It’s going to cut down on screening and it’s also going to make these tests more available. So we’re recommending using these blood tests to screen for amyloid status, not independently, but as a first step.
Another use in specialty clinics, in memory clinics who are prepared to use this and interpret this, these tests, is to start to use them for clinical diagnosis. And again, you could go on for those that are positive and get additional confirmation with a PET scan or CSF, but blood biomarkers can be used to confirm Alzheimer’s disease. So again, we’re recommending gaining more clinical experience with this, using it properly as an initial test with confirmation, if indicated.
Other uses for the blood biomarkers are they may be a good predictor of who’s responding to treatment as we have more treatments and also who is more likely to show progression of memory loss. And so they can be used to help guide treatment and we hope eventually. We need more information about this, but this is certainly worth exploring. And a number of trials have shown … There’s another blood test called Ptau-217 or Ptau-181. These are two forms of tau that are detectable in the blood. And those correlate very well with amyloid plaques in the brain. And also that test seems to go down when the amyloid plaques are lower. And so it may indicate we need more data about this, that someone is responding to the treatment and especially if it’s associated with a clinical benefit.
So there are uses right now as a first step in the screening process or in the diagnostic process. We hope as more information becomes available, that we can use them independently, we won’t need to confirm them with a more expensive test. I see that coming. It’s not far away. And the most important thing is really building the bridge between primary and specialty care, because this is a test that I envision will happen in the primary care setting. Someone goes to see their doctor. They say, they’re concerned about their memory. They have a simple evaluation there, an initial evaluation there. And then if the doctor feels like, yeah, there could be something amiss here, could be Alzheimer’s, let’s test for that, they’ll be able to initiate that. And then if it’s positive, then they can refer to a specialty center for further diagnostic workup if needed and then potentially disease modifying treatments.
So this is the way of the future. Now is the time for us to get experience with this. That’s why we publish these recommendations. But building that bridge between primary and specialty care is really going to benefit patients with Alzheimer’s and help us detect cases much earlier than we’re doing currently. So, that’s really important.
Dr. Salloway was the co-chair of the Investigator Steering Committee for the Aducanumab phase 3 program and he served as a site PI for the aducanumab and lecanemab phase 3 studies, the donanemab phase 2 trial and he was the Project Arm Leader for gantenerumab in DIAN-TU. He has received consulting income from Biogen, Lilly, Roche, Genentech, Bolden, Amylyx, Prothena and Eisai. He has no stock or royalties related to any medication in development. Dr. Salloway serves on the planning committee for the National Disease Modifying Treatment and Diagnostic Registry Work Group and he is a member of the ADRD Therapeutics Work Group. He is the first author for the report of ARIA in aducanumab phase 3 (Salloway, JAMA Neurology, 2022), the report of gantenerumab and solanezumab in DIAN-TU (Salloway, Nature Medicine, 2021). He is a co-author on the report of the donanemab phase 2 trial (Mintun, NEJM, 2021) and the Aducanumab Appropriate Use Recommendations (Cummings, Journal of the Prevention of Alzheimer’s Disease, 2021).